Ultraviolet (UV) radiation from sunlight can lead to multiple adverse effects including cutaneous phototoxicity (sunburn), photoaging, and carcinogenesis (Federman et al., JAMA 312:87-88 (2014); Stern et al, Journal of the American Academy of Dermatology 44:755-761 (2001)). UVB directly induces cyclopyrimidine dimers (CPDs) within the genomic DNA (gDNA) of keratinocytes, and both UVA and UVB exposure markedly enhance production of reactive oxidation species (ROS) that damage a variety of cellular components, including gDNA (Gilchrest, B. A. The Journal of Investigative Dermatology 133:E2-6 (2013)), and induce immunosuppressive cytokines (Schwarz and Luger, Journal of Photochemistry and Photobiology. B, Biology 4:1-13 (1989)). UV-exposure is clearly linked to both melanoma and non-melanoma skin cancer development (Gordon et al, Facial Plastic Surgery: FPS 29:402-410 (2013)). Over the past few decades, commercially available UV-protective sunblocks have largely incorporated organic UV filters [e.g. avobenzone, octinoxate, octocrylene, oxybenzone and padimate O (PO) (Hayden et al., Skin Pharmacol. Physiol. 18:170-174 (2005)] as formulations based on oil/water emulsions (Quatrano and Dinulos, Curr. Opin. Pediatr. 25:122-129 (2013)). There are substantial concerns, however, that these aromatic organic compounds can penetrate through the stratum corneum, or via follicles, into epidermal cells, keratinocytes and Langerhans cells (Hayden et al., Skin Pharmacol. Physiol. 18:170-174 (2005)). The potential for systemic absorption of such organic compounds, and their depot in adipose tissue, has also been a concern (Gulston and Knowland, Mutat Res-Gen Tox En 444:49-60 (1999); Hanson et al., Free Radical Biology and Medicine 41:1205-1212 (2006); Bastien et al., The Journal of Investigative Dermatology, 130:2463-2471 (2010); Krause et al., Int. J. Androl. 35:424-436 (2012)).
Alternatively, UV-blocking inorganic materials such as micronized zinc oxide (ZnO) and titanium dioxide (TiO2) particles (Barnard, Nature Nanotechnology, 5:271-274 (2010)) have been utilized. While transdermal penetration of the inorganic particles appears to be less of a concern than for the organic agents, both types of sunblock agents have shown the capacity to enhance ROS generation after UV exposure, suggesting even small quantities may contribute to cellular damage and ultimately carcinogenesis (Pan et al., Small, 5:511-520 (2009); Trouiller et al., Cancer Res. 69:8784-8789 (2009); Wu et al., Toxicology Letters, 191:1-8 (2009); Zhang et al., Journal of Biomedical Nanotechnology, 10:1450-1457 (2014)). Thus, while the application of such products protects against sunburn, e.g. raises the skin's minimal erythema dose (MED), there continues to be controversy regarding their overall effectiveness in preventing skin cancer (Krause et al., Int. J. Androl. 35:424-436 (2012); Planta, Journal of the American Board of Family Medicine: JABFM, 24:735-739 (2011); Lindqvist et al., J. Intern. Med. 276:77-86 (2014); Plourde, E. Sunscreens—Biohazard: Treat As Hazardous Waste. (New Voice Publications (2011)). Moreover, several UV filters have been detected in human urine and breast milk samples after tropical treatment, and may mediate systemic effects including endocrine disruption (Hayden et al., Skin Pharmacol. Physiol. 18:170-174 (2005); Krause et al., Int. J. Androl. 35:424-436 (2012); Hayden et al., Lancet, 350:863-864 (1997)). Therefore, preventing direct skin contact and subsequent epidermal penetration may be essential to eliminating the potential adverse effects of sunscreens.
Some commercially available sunscreens are opaque, due to their use of large particles (Barnard, Nature Nanotechnology, 5:271-274 (2010)). The smaller, non-adhesive nanoparticles used in other commercially available sunscreens accumulate in hair follicles or penetrate deep into dermis, causing a variety of adverse effects (Vemula et al., Nature Nanotechnology, 6:291-295 (2011); Kimura et al., Biol. Pharm. Bull. 35:1476-1486 (2012)). Numerical simulations of nanoparticle properties suggest that unless small nanoparticles can be clearly demonstrated as safe, it is increasingly difficult to solve this paradox (Barnard, Nature Nanotechnology, 5:271-274 (2010)). (Mitragotri et al., Nature Reviews. Drug discovery, 13:655-672 (2014); Zakrewsky et al., Proc. Natl. Acad. Sci. U.S.A. 111:13313-13318 (2014); Zheng et al., Proc. Natl. Acad. Sci. U.S.A. 109:11975-11980 (2012); Gu and Roy, J Drug Deliv Sci Tec. 14:265-273 (2004)).
Commercial sunscreens polymerize monomers with an initiator in order to stabilize the UV filters into a film that coats the skin. The chemicals involved include a variety of acrylate derivatives and multiple initiators (Nair et al., Pigment Cell and Melanoma Research 27:843-845 (2014), which have been implicated in irritant and allergic contact dermatitis (Bennassar et al., Dermatology Online Journal 15:14 (2009); Rietschel, R. L. Fisher's Contact Dermatitis. (Pmph Usa; 6 edition (Apr. 2, 2007)).
It is therefore an object of the present invention to provide improved sunblock particles for use in sunscreens.